December 19, 2010

Treatment of Chronic Hepatitis C Patients with the NS3/4A Protease Inhibitor Danoprevir (ITMN-191/RG7227) Leads to Robust Reductions in Viral RNA: A Phase 1b Multiple Ascending Dose Study

J Hepatol. 2010 Dec 8. [Epub ahead of print]

Forestier N, Larrey D, Guyader D, Marcellin P, Rouzier R, Patat A, Smith P, Bradford W, Porter S, Blatt L, Seiwert SD, Zeuzem S.

J.W. Goethe Universität, Frankfurt, Germany.

Abstract

Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. Four cohorts of treatment-naïve (TN) patients (100 mg q12h, 100 mg q8h, 200 mg q12h, 200 mg q8h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12h) were investigated. RESULTS: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and without association to treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were -3.9 log(10) IU/mL and -3.2 log(10) IU/mL in TN receiving 200 mg q8h and 200 mg q12h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10) IU/mL of viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with R155K substitution in NS3 regardless of HCV subtype. CONCLUSION: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/mL reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145848 [PubMed - as supplied by publisher]

Source

No comments:

Post a Comment